Pneumocystis carinii interacts with glycoproteins present in the lower respiratory tract through its mannose-rich surface antigen complex termed gpA. Surfactant protein D (SP-D) is a recently described component of the airspace lining material that possesses a calcium-dependent lectin domain capable of interacting with glycoconjugates present on microorganisms and leukocytes. Accordingly, we evaluated the extent and localization of SP-D in the lower respiratory tract during Pneumocystis pneumonia in an immunosuppressed rat model and examined its role in modulating interaction of P. carinii with macrophages. We report that SP-D is a major component of the alveolar exudates that typify P. carinii pneumonia and is present bound to the surface of P. carinii organisms in vivo. We further demonstrate that SP-D binds to P. carinii through saccharide-mediated interactions with gpA present on the surface of the organism. Lastly, we show that SP-D augments binding of P. carinii to alveolar macrophages, but does not significantly enhance macrophage phagocytosis of the organism. The interaction of SP-D with gpA represents an additional important component of the host-parasite relationship during P. carinii pneumonia.